Many transcription factors are sequence-specific DNA-binding proteins. In general, transcription factors contain two functional domains, one for DNA-binding and one for transcriptional activation or suppression. These functions often reside within structural domains that retain their function when removed form their natural context. The DNA-binding domains of transcription factors falls into several structural families based on their primary amino acid sequence. Examples of families include the helix-tuml-helix, zinc finger, leucine zipper, and helix-loop helix proteins.
Helix-turn-helix proteins have a protein helix which lies across the major grove of the DNA helix and makes contact with exposed base pairs. These proteins contain a second helix that lies across the first and contacts other proteins in the transcription apparatus. Zinc finger proteins have a repeated motif of cysteine and histidine that are thought to fold up into a three-dimensional structure coordinated by a zinc ion. Examples of zinc finger proteins are Sp1, and steroid receptor proteins. Leucine zipper proteins have repeats of four of five leucine residues precisely seven amino acids apart which provide hydrophobic faces though which the proteins can form dimers. Adjacent to the leucine zipper is a domain enriched for positively charged amino acids, arginine and lysine. This DNA-binding domain is amino terminal to the leucine zipper. Examples of leucine zippers are c-fos and c-jun. Helix-loop-helix proteins are similar to the leucine zipper family as they bind DNA as homo- or heterodimers. Helix-loop-helix proteins also have a positively charged domain that recognizes the DNA. Examples of helix-loop-helix proteins are Myol) and c-myc. These categories of transcription factors are not absolute; there are many transcription factors that do not fall into any of these categories.
The regions of transcription factors required for regulating transcription once the DNA-binding domain brings the factor in close contact with the DNA are called "activation domains" or "suppression domains." These domains are less well characterized than the DNA-binding domains. In some proteins, the activation domain has a net negative charge. However, many potent transcription factors lack acidic regions; the biochemical characteristics of these proteins is not yet understood. At present, most theories of how proteins interact to regulate transcription are highly speculative (for review of transcription factors see: DNA: A Short Course, second edition, J. D. Watson et al. (eds), W. H. Freeman and Co., N.Y., 1992, pp. 161-168).
Fibroblast growth factors are a family of related proteins, most of which initiate fibroblast proliferation. The FGF family includes nine members (FGF1-9), all of which are characterized by an internal 120 amino acid sequence that allows for growth factor binding to cell surface receptors (e.g., Coulier, F., et al., 1994, Prog. Growith acclor Res. 5:1). Considerable species crossreactivity has been reported for FGF 1-7 and 9 (e.g., Mathieu, M., et al., 1995, Ann. Rev. Biochen. 58:575). FGF-2 (or basic FGF) induces proliferation of fibroblasts, endotlhelial cells, condrocytes, smooth muscle, and melanocytes. It has also been found to induce adipocyte differentiation, stimulate astrocyte migration, and prolong neuron survival (Burgess, W. H., and Maciag, T., 1989, Ann. Rev. Biochem. 58:575). It has been proposed that FGF-2 plays a role in angiogenesis (reviewed in: Slavin, J Cell Biol. Int. 19:431-444), wound healing, tissue repair, embryonic development, differentiation, neuronal function and neuronal degeneration. Additionally FGF-2 may participate in the production of a variety of pathological conditions resulting from excessive cell proliferation and excessive angiogenesis. For example, FGF-2 is associated with pituitary lactotropli tumorigenesis (Schwcppe, R. E., et al., 1997, J. Biol. Chem. 272:30852-9), melanoma (Halaban, R., 1996, Semin. Oncol. 23: 673-81)), and astrocytoma (Morrison, R. S., et al., 1994, J Neuroncol. 18:207-16).
Wound healing is a complex and protracted process of tissue repair and remodeling involving many different cell types that require a finely tuned control of various biochemical reaction cascades to balance degradative and regenerative processes. Among other things the process comprises the migration of different cell types into the wound region, growth stimulation of epithelial cells and fibroblasts, formation of new blood vessels, and the generation of a new extracellular matrix. At all phases correct functioning critically depends on the biological activities of various cytokines, including chemokines, FGF, FGF-1, FGF-2, IGF, PDGF, and TGF. Animal experiments and clinical experience have demonstrated that the topical administration of various cytokines, including FGF-2, FGF, KGF, PDGF, TGF-.beta., either alone or in combination, considerably accelerates wound healing.